Postnatal corticosteroid use for prevention or treatment of Bronchopulmonary Dysplasia in England and Wales 2012-2019: a retrospective population cohort study

Objective: Describe the population of babies who do and do not receive postnatal corticosteroids for prevention or treatment of bronchopulmonary dysplasia (BPD). Design: Retrospective cohort study using data held in the National Neonatal Research Database. Setting: National Health Service neonatal units in England and Wales. Patients: Babies born less than 32 weeks gestation and admitted to neonatal units from 1 January 2012 to 31 December 2019. Main outcomes: Proportion of babies given postnatal corticosteroid; type of corticosteroid; age at initiation and duration, trends over time. Secondary outcomes: Survival to discharge, treatment for retinopathy of prematurity, BPD, brain injury, severe necrotising enterocolitis, gastrointestinal perforation. Results: 8% (4713/62019) of babies born <32 weeks and 26% (3525/13527) born <27 weeks received postnatal corticosteroids for BPD. Dexamethasone was predominantly used 5.3% (3309/62019), followed by late hydrocortisone 1.5%, inhaled budesonide 1.5%. prednisolone 0.8%, early hydrocortisone 0.3% and methylprednisolone 0.05%. Dexamethasone use increased over time (2012: 4.5 vs 2019: 5.8%, p=0.04). Median postnatal age of initiation of corticosteroid course was around 3 weeks for late hydrocortisone, 4 weeks for dexamethasone, 6 weeks for inhaled budesonide, 12 weeks for prednisolone and 16 weeks for methylprednisolone. Babies who received postnatal corticosteroids were born more prematurely, had a higher incidence of comorbidities and a longer length of stay. Conclusions: In England and Wales, around 1 in 12 babies born less than 32 weeks and 1 in 4 born less than 27 weeks receive postnatal corticosteroids to prevent or treat BPD. Given the lack of convincing evidence of efficacy, challenges of recruiting to and length of time taken to conduct randomised controlled trial, our data highlight the need to monitor long-term outcomes in children who received neonatal postnatal corticosteroids

Outcomes following early parenteral nutrition use in preterm neonates: Protocol for an observational study

Introduction Preterm babies are among the highest users of parenteral nutrition (PN) of any patient group, but there is wide variation in commencement, duration, and composition of PN and uncertainty around which groups will benefit from early introduction. Recent studies in critically unwell adults and children suggest that harms, specifically increased rates of nosocomial infection, outweigh the benefits of early administration of PN. In this study, we will describe early PN use in neonatal units in England, Wales and Scotland. We will also evaluate if this is associated with differences in important neonatal outcomes in neonates born between 30+0 and 32+6 weeks+days gestation. Methods and analysis We will use routinely collected data from all neonatal units in England, Wales and Scotland, available in the National Neonatal Research Database (NNRD). We will describe clinical practice in relation to any use of PN during the first 7 postnatal days among neonates admitted to neonatal care between 1 January 2012 and 31 December 2017. We will compare outcomes in neonates born between 30+0 and 32+6 weeks+days gestation who did or did not receive PN in the first week after birth using a propensity score-matched approach. The primary outcome will be survival to discharge home. Secondary outcomes will include components of the neonatal core outcome set: outcomes identified as important by former patients, parents, clinicians and researchers. Ethics and dissemination We have obtained UK National Research Ethics Committee approval for this study (Ref: 18/NI/0214). The results of this study will be presented at academic conferences; the UK charity Bliss will aid dissemination to former patients and parents

Early antibiotic use and incidence of necrotising enterocolitis in very preterm infants: a protocol for a UK based observational study using routinely recorded data

Introduction Necrotising enterocolitis (NEC) remains a major contributor to preterm mortality and morbidity. Prolonged duration of antibiotic therapy after delivery is associated with later NEC development but recent evidence suggests that absence of antibiotic treatment after delivery may also increase NEC risk. We will explore this controversy using a large pre-existing dataset of preterm infants in the UK. Methods and analysis: This is a retrospective cohort study using data from UK National Neonatal Research Database (NNRD) for infants born 1 January 2012 to 31 December 2020. Eligible infants will be <32 weeks gestation, alive on day 3. Primary outcome is development of severe NEC, compared in infants receiving early antibiotics (days 1–2 after birth) and those not. Subgroup analysis on duration of early antibiotic exposure will also occur. Secondary outcomes are: late onset sepsis, total antibiotic use, predischarge mortality, retinopathy of prematurity, intraventricular haemorrhage, bronchopulmonary dysplasia, focal intestinal perforation and any abdominal surgery. To address competing risks, incidence of death before day 7, 14 and 28 will be analysed. We will perform logistic regression and propensity score matched analyses. Statistical analyses will be guided by NEC risk factors, exposures and outcome presented in a causal diagram. These covariates include but are not limited to gestational age, birth weight, small for gestational age, sex, ethnicity, delivery mode, delivery without labour, Apgar score, early feeding and probiotic use. Sensitivity analyses of alternate NEC definitions, specific antibiotics and time of initiation will occur. Ethics and dissemination: We will use deidentified data from NNRD, which holds permissions for the original data, from which parents can opt out and seek study-specific research ethics approval. The results will help to determine optimal use of early antibiotics for very preterm infants. Implications: This data will help optimise early antibiotic use in preterm infants. Trial registration number: ISRCTN55101779

Outcomes in relation to early parenteral nutrition use in preterm neonates born between 30 and 33 weeks gestation: a propensity score matched observational study

Objective To evaluate whether in preterm neonates parenteral nutrition use in the first seven postnatal days, compared with no parenteral nutrition use, is associated with differences in survival and other important morbidities. Randomised trials in critically ill older children show that harms, such as nosocomial infection, outweigh benefits of early parenteral nutrition administration; there is a paucity of similar data in neonates. Design Retrospective cohort study using propensity matching including 35 maternal, infant and organisational factors to minimise bias and confounding. Setting National, population-level clinical data obtained for all National Health Service neonatal units in England and Wales. Patients Preterm neonates born between 30+0 and 32+6 weeks+days . Interventions The exposure was parenteral nutrition administered in the first seven days of postnatal life; the comparator was no parenteral nutrition. Main outcome measures The primary outcome was survival to discharge from neonatal care. Secondary outcomes comprised the neonatal core outcome set. Results 16,292 neonates were compared in propensity score matched analyses. Compared with matched neonates not given parenteral nutrition in the first postnatal week, neonates who received parenteral nutrition had higher survival at discharge (absolute rate increase 0.91%; 95% CI 0.53% to 1.30%), but higher rates of necrotising enterocolitis (absolute rate increase 4.6%), bronchopulmonary dysplasia (absolute rate increase 3.9%), late-onset sepsis (absolute rate increase 1.5%) and need for surgical procedures (absolute rate increase 0.92%). Conclusions In neonates born between 30+0 and 32+6 weeks gestation, those given parenteral nutrition in the first postnatal week had a higher rate of survival but higher rates of important neonatal morbidities. Clinician equipoise in this area should be resolved by prospective, randomised trials

A genome-wide CRISPR activation screen identifies

The genome is pervasively transcribed to produce a vast array of non-coding RNAs (ncRNAs). Long non-coding RNAs (lncRNAs) are transcripts of \u3e200 nucleotides and are best known for their ability to regulate gene expression. Enhancer RNAs (eRNAs) are subclass of lncRNAs that are synthesized from enhancer regions and have also been shown to coordinate gene expression. The biological function and significance of most lncRNAs and eRNAs remain to be determined. Epithelial to mesenchymal transition (EMT) is a ubiquitous cellular process that occurs during cellular migration, homeostasis, fibrosis, and cancer-cell metastasis. EMT- transcription factors, such as SNAI1 induce a complex transcriptional program that coordinates the morphological and molecular changes associated with EMT. Such complex transcriptional programs are often subject to coordination by networks of ncRNAs and thus can be leveraged to identify novel functional ncRNA loci. Here, using a genome-wide CRISPR activation (CRISPRa) screen targeting ~10,000 lncRNA loci we identified ncRNA loci that could either promote or attenuate EMT. We discovered a novel locus that we named SCREEM (SNAI1 cis-regulatory eRNAs expressed in monocytes). The SCREEM locus contained a cluster of eRNAs that when activated using CRISPRa induced expression of the neighboring gene SNAI1, driving concomitant EMT. However, the SCREEM eRNA transcripts themselves appeared dispensable for the induction of SNAI1 expression. Interestingly, the SCREEM eRNAs and SNAI1 were co- expressed in activated monocytes, where the SCREEM locus demarcated a monocyte-specific super-enhancer. These findings suggest a potential role for SNAI1 in monocytes. Exploration of the SCREEM-SNAI axis could reveal novel aspects of monocyte biology

A randomised controlled trial of high vs low volume initiation and rapid vs slow advancement of milk feeds in infants with birthweights 1000 g in a resource-limited setting

Background: Optimal feeding regimens for infants ≤ 1000 g have not been established and are a global healthcare concern. Aims and objectives: A controlled trial to establish the safety and efficacy of high vs low volume initiation and rapid vs slow advancement of milk feeds in a resource-limited setting was undertaken. Methods: Infants ≤ 1000 g birthweight were randomised to one of four arms, either low (4 ml/kg/day) or high (24 ml/kg/day) initiation and either slow (24 ml/kg/day) or rapid (36 ml/kg/day) advancement of exclusive feeds of human milk (mother’s or donor) until a weight of 1200 g was reached. After this point, formula was used to supplement insufficient mother’s milk. The primary outcome was time to reach 1500 g. Results: infants were recruited (51: low/slow; 47: low/rapid; 52: high/slow; 50: high/rapid). Infants on rapid advancement regimens reached 1500 g most rapidly (hazard ratio 1.48, 95% CI 1.05–2.09, P=0.03). The rapid advancement groups also regained birthweight more rapidly (hazard ratio 1.77, 95% CI 1.26–2.50, P=0.001). There was no apparent effect of high vs low initiation volumes but there was some evidence of interaction between interventions. There were no significant differences in other secondary outcomes, including necrotising enterocolitis, feed intolerance and late-onset sepsis. Conclusions: In this small pilot study, higher initiation feed volumes and larger daily increments appeared to be well tolerated and resulted in more rapid early weight gain. These data provide justification for a larger study in resource-limited settings to address mortality, necrotising enterocolitis and other important outcomes

Growth of a cohort of very low birth weight infants in Johannesburg, South Africa

<p>Abstract</p> <p>Background</p> <p>Little is known about the growth of VLBW infants in South Africa. The aim of this study was to assess the growth of a cohort of VLBW infants in Johannesburg.</p> <p>Methods</p> <p>A secondary analysis of a prospective cohort was conducted on 139 VLBW infants (birth weight ≤1500 g) admitted to Charlotte Maxeke Johannesburg Academic Hospital. Growth measurements were obtained from patient files and compared with the World Health Organization Child Growth Standards (WHO-CGS) and with a previous cohort of South African VLBW infants. The sample size per analysis ranged from 11 to 81 infants.</p> <p>Results</p> <p>Comparison with the WHO-CGS showed initial poor growth followed by gradual catch up growth with mean Z scores of 0.0 at 20 months postmenstrual age for weight, -0.8 at 20 months postmenstrual age for length and 0.0 at 3 months postmenstrual age for head circumference. Growth was comparable with that of a previous cohort of South African VLBW infants in all parameters.</p> <p>Conclusions</p> <p>Initial poor growth in the study sample was followed by gradual catch up growth but with persistent deficits in length for age at 20 months postmenstrual age relative to healthy term infants.</p

Sexual dimorphism in relation to adipose tissue and intrahepatocellular lipid deposition in early infancy

Sexual dimorphism in adiposity is well described in adults, but the age at which differences first manifest is uncertain. Using a prospective cohort, we describe longitudinal changes in directly measured adiposity and intrahepatocellular lipid (IHCL) in relation to sex in healthy term infants. At median ages of 13 and 63 days, infants underwent quantification of adipose tissue depots by whole-body magnetic resonance imaging and measurement of IHCL by in vivo proton magnetic resonance spectroscopy. Longitudinal data were obtained from 70 infants (40 boys and 30 girls). In the neonatal period girls are more adipose in relation to body size than boys. At follow-up (median age 63 days), girls remained significantly more adipose. The greater relative adiposity that characterises girls is explained by more subcutaneous adipose tissue and this becomes increasingly apparent by follow-up. No significant sex differences were seen in IHCL. Sex-specific differences in infant adipose tissue distribution are in keeping with those described in later life, and suggest that sexual dimorphism in adiposity is established in early infancy

Nutritional Evaluation and Optimisation in Neonates (NEON) trial of amino acid regimen and intravenous lipid composition in preterm parenteral nutrition: a randomised double-blind controlled trial

Background Parenteral nutrition (PN) is central to the care of very immature infants. Early intakes of higher amounts of amino acids and the use of lipid emulsions containing fish oils are recommended by current international recommendations. Objective To confirm the safety and demonstrate efficacy of the immediate introduction of the recommended daily intake of amino acids (Imm-RDI) and soya bean oil, medium-chain triglycerides, olive oil and fish oil lipid in PN to increase non-adipose (lean) body mass and decrease intrahepatocellular lipid (IHCL) content. Design Multicentre, double-blind, 2 × 2 factorial and randomised controlled trial (RCT). Setting Neonatal units in London and south-east England, UK. Participants Extremely preterm infants born before 31 weeks of gestation without major congenital or life-threatening abnormalities who could to be randomised to receive PN within 24 hours of birth. Interventions Infants were randomised within 24 hours of birth to receive PN containing either high [RDI of amino acids (Imm-RDI)] or low [incremental amino acids (Inc-AA) control] levels of amino acids. In addition, infants were randomised to receive either 20% SMOFlipid® (Fresenius Kabi AG, Richmond Hill, ON, Canada) or 20% Intralipid® (Fresenius Kabi AG, Richmond Hill, ON, Canada) (control). This resulted in four groups: (1) Inc-AA/Intralipid, (2) Inc-AA/SMOFlipid, (3) Imm-RDI/Intralipid and (4) Imm-RDI/SMOFlipid. The intervention was continued until infants were receiving 150 ml/kg/day of enteral feeds for 24 hours. Primary outcome measure For the amino acid intervention, this was non-adipose or lean body mass measured by magnetic resonance imaging. For the lipid composition intervention, this was IHCL content as measured by hepatic magnetic resonance spectroscopy. Primary outcomes were measured at term age equivalent, between 37 and 44 weeks postmenstrual age. Results We randomised 168 infants born before 31 weeks of gestation. We evaluated outcomes, at term, in 133 infants. There were no significant differences in non-adipose mass between the Imm-RDI and Inc-AA groups [adjusted mean difference 1.0 g, 95% confidence interval (CI) –108 to 111 g] or in levels of IHCLs between the SMOFlipid and Intralipid groups (adjusted mean SMOFlipid to Intralipid ratio 1.1, 95% CI 0.8 to 1.6). Infants receiving the Imm-RDI were more likely than Inc-AA infants to have blood urea nitrogen levels > 7 mmol/l [75% vs. 49% (p  10 mmol/l [49% vs. 18% (p < 0.01)]. Furthermore, head circumference at term was smaller in the Imm-RDI group (mean difference –0.8 cm, 95% CI –1.5 to –0.1 cm; p = 0.02). There were no significant differences in any prespecified secondary outcomes, including adiposity, liver function tests, weight, length and mortality. Limitations Not all eligible babies were available for recruitment, as pharmacy staff trained in clinical trial procedures were unavailable at weekends in three of the four centres. We were able to assess brain volumes in only one-third of participants, as imaging was carried out while the participants were sleeping naturally and we measured primary outcomes first and continued to brain imaging only if the infant remained asleep. Conclusions Immediate delivery of the recommended daily intake of parenteral amino acids does not benefit body composition or growth to term and may be harmful; SMOFlipid does not affect IHCL content. Future work The long-term functional outcomes of early administration of RDI of amino acids and the use of SMOFlipid, including neurodevelopment, body composition and metabolic health, should be evaluated. Trial registration Current Controlled Trials ISRCTN29665319 and EudraCT 2009-016731-34. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership